WO2018121585A1 - Nanoassembly of hypocrellin derivative and application thereof - Google Patents

Abstract

A nanoassembly of a hypocrellin derivative, prepared by using a hypocrellin derivative and an amphiphile as precursors, and utilizing the self-assembly property between the amphiphile and the hypocrellin molecule to obtain the nanoassembly with a size of 20-200 nm and a maximum absorption wavelength range of 650-850 nm. The obtained nanoassembly can be used as a photosensitizer agent in photodynamic therapy for treating a tumor.

Description

Hypocrellin derivative nano assembly and application thereof Technical field

The invention relates to the field of nanophotosensitive agent medicines for photodynamic therapy. More specifically, it relates to a hypocrellin derivative nanoassembly and use thereof.

Background technique

Photodynamic Therapy (PDT) is a new treatment technology for cancer and other major diseases in recent years. It is a new disease treatment method based on the interaction of light, photosensitizer and oxygen. Specifically, the light-irradiated photosensitizer enriched in tumor tissue produces reactive oxygen species, and the active oxygen kills efficiently. Nearby tumor cells, thereby producing a therapeutic effect on diseased tissues such as tumors. Photodynamic therapy has become the fourth tumor treatment method after surgery, radiotherapy and chemotherapy. Its advantage lies in its selectivity, high efficiency and safety, which reduces the damage to normal cells and greatly reduces the side effects. At present, photodynamic therapy has not only achieved great achievements in the clinical treatment of cancer, but also widely used in the treatment of non-tumor diseases such as genital warts, psoriasis, port wine stains, rheumatoid arthritis, and fundus macular degeneration.

Hypocrellin is a natural photosensitizer extracted from a parasitic fungus, Rhodobacter sphaeroides, on the bamboo stalk of Yunnan Province at an altitude of 4,000 meters. It mainly includes Hypocrellin A (HA) and Rhodobacter sinensis. Hypocrellin B (HB) has good phototoxicity, low dark toxicity, fast metabolism in the body and clear chemical structure. It is a promising photosensitizer. However, the main absorption wavelength of lutein is in the range of 450-550 nm, and this wavelength can penetrate less than 1 mm, and the light absorption ability is weak in the phototherapy window (600-900 nm). Over the past decade or so, many chemical modifications to heparin have sought to extend its absorption wavelength to the phototherapy window (New J. Chem., 2002, 26, 1130–1136; J. Org. Chem. 2003). , 68, 2048-2050; 2001, 61, 122-128; Photochem. Photobiol., 2001, 74, 143-148; Dyes and Pigments, 1999, 41, 93-100; Bioorg. Med. Chem. Let., 2004, 14, 1499 -1501; 2012, 22, 5003-5007). At present, the researchers found that the maximum absorption wavelength of n-butylamamine-modified hypocrein was significantly red-shifted to 600-650 nm (Photochem. Photobiol., 2003, 78, 411-415; Bioorg. Med. Chem. Let., 2011, 11 , 2045-2047; J. Photochem. Photobiol. B: 1998, 44, 21-28). However, such compounds are relatively poor in water solubility and biocompatibility.

Conventional organic photosensitizer molecules, including hypocrellin derivatives, generally have poor anti-bleaching ability, low photostability, and poor targeting to the lesion site after intravenous injection, thereby reducing the therapeutic effect of the disease. Nano-photosensitive agent (20-200nm in size) is a new generation of photosensitizer formed by loading or coating traditional photosensitizers with nano-materials such as up-conversion nanoparticles and silica. It has high photostability and can be passively targeted to reach the lesion. Advantages such as sites are expected to overcome the shortcomings of conventional organic photosensitizers (Zhang Yong et al, Nanoparticles in Photodynamic Therapy Chem. Rev. 2015, 115, 1990-2042). However, the toxicity of the nano photosensitizer itself and the difficulty of metabolism are the bottlenecks of such photosensitization for clinical application. The self-assembly technology of amphiphilic drug molecules developed in recent years has opened up a new way for clinical application of nano-photosensitive drugs (Cui Honggang et al, Building nanostructures with drugs, Nano Today (2016) 11, 13-30; Nie Zhihong et Concurrent Self-assembly of amphiphiles into nanoarchitectures with increasing complexity Nano Today (2015) 10, 278-300).

At present, on the one hand, despite the research of hypocrellin-micelle (Chinese patent CN101002757A), liposome (Chinese patent CN101371828A), and water-soluble nanoparticle (Chinese patent CN1565433A), important progress has been made. However, there are still some shortcomings, such as the stability of the micelle system and the targeting of the lesion tissue; the stability of the liposome and the water-soluble hyalin nanoparticles containing surfactants and long-wavelength photodynamic effects are still urgently needed. solve. On the other hand, the water-soluble assembly, which is between 20 and 200 nanometers in size, enters the living blood circulation system after intravenous injection and can be concentrated in the lesion by active or passive targeting. More importantly, the preparation of asbestos-like nanovesicles, nanotubes, nanorods and nanosheets and other applications as phototherapy drugs have not been reported.

Therefore, the present invention is derived from a multi-substituted near-infrared erythromycin derivative, a long-chain quaternary ammonium-containing erythromycin derivative, and an ester-water amphiphilic erythromycin derivative. And other amphiphilic medical polymers as raw materials, invented a kind of hyalin derivatives nano-assembler photosensitizer with good water solubility and long-wavelength absorption characteristics, which is used as a photodynamic preparation for intravenous injection to treat tumors. disease.

Summary of the invention

It is an object of the present invention to provide a hypocrellin derivative nanoassembly.

A second object of the present invention is to provide a method for preparing a hypocrellin derivative nano assembly

A third object of the present invention is to provide an application of a rhodamine derivative nanoassembly.

In order to achieve the above first object, the present invention adopts the following technical solutions:

A nano-assembler of hypocrellin derivative, which is a precursor of hypocrellin derivative, and adopts self-assembly property of hypocrellin derivative, and the prepared size is 20-200 nm, and the maximum absorption wavelength range is Nano assembly of 650-850 nm.

Preferably, the hypocrellin derivative nanoassembly is prepared by using a erythromycin derivative and a parent molecule as a precursor, and using a self-assembly property between the amphiphilic molecule and the hyalin molecule, the size is 20 A nanoassembly of -200 nm with a maximum absorption wavelength in the range of 650-850 nm.

The hypocrellin derivative nano-assembly of the invention has good photostability, strong anti-bleaching ability and better biocompatibility; the size is between 20-200 nm, and the blood enters the living body after intravenous injection. The circulatory system can be concentrated in the lesion by active or passive targeting; it can effectively produce reactive oxygen species under the stimulation of near-infrared light (650-850 nm), which can kill tumor cells.

Preferably, the nanoassembly is a nanosphere, a nanorod, a nanotube, a nanosheet, a nanocapsule or a nanocapsule.

Preferably, the hypocrellin derivative is a polysubstituted near-infrared lutein derivative, a hyalin derivative containing a long-chain quaternary ammonium salt or an ester water amphiphilic hyphalin derivative.

Preferably, the amphiphilic molecule is a high molecular polymer, a protein, a polypeptide, a deoxyribonucleic acid (DNA) or a nucleic acid aptamer, and has a molecular weight of between 1,000 and 100,000.

Preferably, the high molecular polymer is polylactic acid-polyethylene glycol (PLGA-PEG), polylactic acid-polyethylene glycol-polylactic acid (PLGA-PEG-PLGA), polyacrylic acid-b-polybutadiene (PAA-b-PB), polyglutamic acid benzyl ester-polyethylene glycol (PBLG-PEG), polystyrene-b-polyvinyl ester (PS-b-PVA), polystyrene-b-poly two Methyl siloxane (PS-b-PPDMS), polystyrene-b-polyethylene glycol dicarboxylate (PS-b-PEN), polyacrylic acid-b-polystyrene (PAA-b-PS) Polystyrene-b polyethylene oxide (PS-b-PPEO) or polydimethylsiloxane-b-polyethylene oxide (PDMS-b-PEO).

Utilizing the parental properties of the amphiphilic molecules, the assembly obtained by the self-assembly technique tends to be superior to the monomer. More importantly, the self-assembly of amphiphilic molecules and drug molecules opens up a new way to improve the delivery capacity of nanomedicines, increase the targeting of lesions or tumor tissues, and reduce side effects.

Preferably, the hypocrellin derivative has the structural formula of formula (1) or formula (2):

In formulas (1) and (2), T ₁ represents that two adjacent R ₂ and R ₃ , R ₄ and R _{5 are} not connected or have one group connected or two groups are connected; when two adjacent R ₂ When R ₃ or R ₄ and R _{5 are} not linked, R ₂ and R ₅ are oxygen, and R ₃ and R ₄ are hydrogen; when two adjacent R ₂ and R ₃ or R ₄ and R ₅ are bonded, They constitute a substituted or unsubstituted six-membered heterocyclic ring, wherein T ₁ is a substituted or unsubstituted linker containing two carbon atoms, R ₂ , R ₅ are nitrogen, R ₃ and R ₄ are sulfur; carbon atoms 13, 14 And the dotted line of 15 digits indicates that the double bond position is in the 13-14 position or the 14-15 position;

In the formula (1), R ₁ is -H, -COCH ₃ or -C(CH ₃ )=N-R; in the formula (2), R ₁ is -H or -COCH ₃ ; T ₂ represents R ₈ and R ₉ linked or unconnected: when R ₈ and R _{9 are} bonded, they form a substituted or unsubstituted five-membered ring, six-membered ring or seven-membered ring, wherein T ₂ is substituted or unsubstituted with one, two or three One carbon atom linker;

When two adjacent R ₂ and R ₃ or R ₄ and R _{5 in the} formula (1) are not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is hydrogen, the double bond is located. C ₁₃ = C ₁₄ or C ₁₄ = C _{15 of} three carbon atoms of C ₁₃ , C ₁₄ , C ₁₅ labeled in formula (1); two adjacent R ₂ and R ₃ or R in formula (1) ₄ and R _{5 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is -COCH ₃ or -C(CH ₃ )=NR, the double bond is located in formula (1) C ₁₃ = C _{14 of} three carbon atoms labeled C ₁₃ , C ₁₄ , C ₁₅ ;

In the formula (2), two adjacent R ₂ and R ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is In the case of hydrogen, the double bond is located at C ₁₃ = C ₁₄ or C ₁₄ = C _{15 of} three carbon atoms of C ₁₃ , C ₁₄ , C ₁₅ labeled in formula (2); two adjacent R in formula (2) ₂ and R ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen and R ₁ is -COCH ₃ , the double bond is at the formula (2) C ₁₃ , C ₁₄ , C ₁₅ three carbon atoms labeled C ₁₃ = C ₁₄ ;

In the formula (1), R is a substituent, and the substituent R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; the hydrophobic group contains an alkyl group, an alkenyl group, Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, phenyl or heterocyclic; the hydrophilic group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a polyethylene glycol a quaternary or quaternary ammonium salt; the structural formula of the substituent R is as shown in formula (3):

In the formula (3), 0≤m≤12, 0≤n≤500, 0≤p≤12, 0≤q≤12, 0≤r≤1; the m, n, p, q, r are zero or a positive integer; Y is a linking group; Z is a terminal group; (OCH ₂ CH ₂ ) _n is a polyethylene glycol unit;

The linking group Y in the formula (3) is NH, O, S, a carboxylate, an amide, a sulfocarboxylate, an aryl group, a heterocyclic aryl group, a hydrocarbon group of 3 to 12 carbon atoms or a cyclic hydrocarbon group of 3 to 12 carbon atoms. ;

The aryl group is a substituted or unsubstituted aryl group; the heterocyclic aryl group is a substituted or unsubstituted heterocyclic aryl group; the hydrocarbon group of 3 to 12 carbon atoms contains a substituted or unsubstituted or hetero atom-containing olefin or alkyne; The cycloalkyl group of 3 to 12 carbon atoms comprises a substituted or unsubstituted or heteroatom-containing cycloalkane, cycloalkene or cycloalkyne; the hetero atom is an oxygen, nitrogen or sulfur atom; the substituent is 1 to 12 carbon atoms An alkyl group, an alkenyl group of 2 to 12 carbon atoms, an alkynyl group of 2 to 12 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an aryl group or an aralkyl group of 6 to 12 carbon atoms; An alkyl group having a hydroxyl group, a carboxylic acid group, a sulfonic acid group or a carboxylic acid ester; or an alkyl group, an alkenyl group, an alkynyl group or a ring having a chain length of 1 to 12 carbon atoms in which the hetero atom is an oxygen, nitrogen or sulfur atom; An alkyl group, an aryl group or an aralkyl group; or a different combination of the above substituents;

The terminal group Z in the formula (3) is hydrogen, an alkyl group of 1 to 12 carbon atoms, an alkoxy group of 1 to 12 carbon atoms, a phenyl group, a heterocyclic ring, a hydroxyl group, a decyl group, a carboxylic acid group, a sulfonic acid group or a pyridine group. salt;

When the terminal group Z in the formula (3) is a pyridinium salt, the substituent on the pyridine ring in the pyridinium salt is in the ortho, meta or para position; the pyridinium salt is composed of pyridine and a chain length of 1-12 The quaternization of a halogenated hydrocarbon of a carbon atom; the anion in the pyridinium salt is an anion permitted by the pharmaceutical preparation;

The three substituents R ₁₂ , R ₁₃ and R _{14 in the} formula (3) are independently or simultaneously: an alkyl group of 1 to 12 carbon atoms, an alkenyl group of 2 to 12 carbon atoms, 2 to 12 carbons. An alkynyl group of an atom, a cycloalkyl group of 3 to 8 carbon atoms, a cycloalkenyl group of 3 to 8 carbon atoms, an aryl group or an aralkyl group of 6 to 12 carbon atoms; or a terminal group containing a hydroxyl group or a carboxylic acid group An alkyl group of a sulfonic acid group or a carboxylic acid ester; or an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or an aralkyl group having a chain length of 1 to 12 carbon atoms containing a hetero atom of oxygen, nitrogen or a sulfur atom; ; or a combination of these different substituents; quaternary ammonium salt of the anion X ^- is the anion of a pharmaceutical formulation allowed;

In the formula (1), two adjacent R ₂ and R ₃ or R ₄ and R _{5 are} not connected and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, R ₁ is -COCH ₃ and a double bond. When C ₁₃ = C ₁₄ , the substituent R in the formula (1) does not comprise the following structure: -(CH ₂ ) _m -NH-(CH ₂ ) _p -Z; wherein 1 ≤ m ≤ 12, 0 ≤ _p ≤ 12, Z is a hydroxyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester.

R ₆ to R ₁₁ on the hypocrellin and piperazine ring in the formula (2) are all subordinate to the substituent R; the substituent R is a hydrophobic group, a hydrophilic group or a hydrophobic group and a hydrophilic group. Different combinations of groups; the hydrophobic group containing an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic group; the hydrophilic group having a hydroxyl group or a carboxyl group , an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycolated group, a quaternary ammonium salt or a pyridinium salt; the structural formula of the substituent R is as shown in the formula (3);

In the formula (2), two adjacent R ₂ and R ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not connected and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is When hydrogen and a double bond are located at C ₁₄ =C ₁₅ , at least one of the two carbon atoms a and b on the piperazine ring of formula (2) is a tertiary carbon atom; two adjacent R ₂ and R in formula (2) ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, R ₁ is -COCH ₃ and the double bond is at C ₁₃ =C ₁₄ . At least one of the two carbon atoms a and b on the piperazine ring of formula (2) is a tertiary carbon atom.

Preferably, the T1 of the hypocrellin derivative in the formula (1) is acyclically linked, and its structural formula is as shown in the formula (4):

In the formula (1), the two adjacent R ₂ and R ₃ or R ₄ and R _{5 of the} erythromycin are not linked and R ₂ and R ₅ are oxygen and R ₃ and R ₄ are hydrogen, and the structural formula thereof As shown in formula (4);

The substituent R ₁ of the hypocrellin derivative in the formula (4) is H, -COCH ₃ or -C(CH ₃ )=NR; when the R ₁ is H, the double bond is in the formula (4) marked C _13, C _14, C ₁₅ of three carbon atoms C ₁₃ = C ₁₄ or C ₁₄ = C _15; said R ₁ is -COCH ₃ or -C (CH ₃₎ = NR, double bond is located C ₁₃ = C _{14 of} three carbon atoms of C ₁₃ , C ₁₄ , and C ₁₅ labeled in the formula (4); preferably, the above structure is represented by the formulas (4a) to (4d):

The structural formula of the substituent R in the formula (4) is as shown in the formula (3), and the substituent R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; The group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic ring; the hydrophilic group contains a hydroxyl group, a carboxyl group, an ester group, an amide group or a carboxylic acid group. , sulfonic acid group, ethylene glycol group or quaternary ammonium salt;

In the above formula (4), the substituent R ₁ is H and the double bond is substituted at the C ₁₄ =C ₁₅ position (formula 4b) or R ₁ is -COCH ₃ and the double bond is at the C ₁₃ =C ₁₄ position (formula 4c). The radical R does not comprise the following structure: -(CH ₂ ) _m -NH-(CH ₂ ) _p -Z; wherein 1 ≤ m ≤ 12, 0 ≤ _p ≤ 12, Z is a hydroxyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester.

Preferably, in the formula (2), both T1 and T2 are non-cyclically connected, and the structural formula is as shown in the formula (5):

In formula (2), two adjacent R ₂ and R ₃ , R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen and R ₃ and R ₄ are Hydrogen, the structural formula of which is represented by formula (5);

The substituent R ₁ of the piperazine derivative of the formula (5) is H or -COCH ₃ ; when the R ₁ is H, the double bond is located at C ₁₃ and C as indicated in the formula (5). ₁₄ , C ₁₃ three carbon atoms of C ₁₃ = C ₁₄ or C ₁₄ = C ₁₅ ; when R ₁ is -COCH ₃ , the double bond is located in the formula (5) labeled C ₁₃ , C ₁₄ , C ₁₅ C ₁₃ = C _{14 of} three carbon atoms; preferably, the above structure is as shown in the formulas (5a) to (5c):

In the above formula (5), when the substituent R ₁ is H and the double bond is at the C ₁₄ =C ₁₅ position, at least one of the two carbon atoms a and b on the piperazine ring of the formula (5b) is a tertiary carbon atom; When (5) the substituent R ₁ is -COCH ₃ and the double bond is at the C ₁₃ =C ₁₄ position, at least one of the two carbon atoms a and b on the piperazine ring of the formula (5c) is a tertiary carbon atom;

The substituents R ₆ to R ₁₁ in the formula (5) are all defined by the substituent R in the formula (3), and the substituents R ₆ to R _{11 are} partially or wholly the same or completely different; the substituent R ₆ ～ R ₁₁ is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; the hydrophobic group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or a heterocyclic ring; The group contains a hydroxyl group, a carboxyl group, an ester group, an ether group, an amide group, a sulfonic acid group, an ethylene glycol unit or a quaternary ammonium salt.

Preferably, T1 in the formula (1) and formula (2) is a substituted or unsubstituted linker having two carbon atoms, and the structure is as shown in the formula (6): wherein the substituents R ₁₅ to R ₁₈ Separately or simultaneously as an R substituent in the formula (3) of claim 1, wherein R ₈ , R ₉ and T 2 in the formula (2) constitute a substituted or unsubstituted five-membered ring, six-membered ring or seven-membered ring When, as shown in equation (7):

Wherein ring A is a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic ring or a non-heterocyclic ring, and the substituents on the ring are independently or simultaneously the R substituent in the formula (3) in claim 1; R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; the hydrophobic group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic ring; the hydrophilic group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycol group or a quaternary ammonium salt;

Preferably, the linker Y in the substituent R in the formula (3) is: -NH-; -O-, -S-; -COO-; CONH-; -SO ₃ -; -CH=CH-; -C≡C-;-C ₆ H ₄ -(phenyl);-C ₆ H ₃ (CH ₃ )-;-C ₆ H ₃ (C ₂ H ₅ )-;-C ₆ H ₃ (OH)- ;-C ₆ H ₃ (F)-; -C ₆ H ₃ (Cl)-; -C ₆ H ₃ (Br)-; -C ₅ H ₃ N-(pyridyl); -C ₃ H ₄ -( Cyclopropyl); -C ₄ H ₆ -(cyclobutyl); -C ₅ H ₈ -(cyclopentyl); -C ₅ H ₇ (CH ₃ )-(methylcyclopentyl); -C ₅ H ₇ (OH)-(hydroxycyclopentyl); -C ₆ H ₁₀ -(cyclohexyl); -C ₆ H ₉ (CH ₃ )-(methylcyclohexyl); -C ₆ H ₉ (C ₂ H ₅ )-(ethylcyclohexyl); -C ₆ H ₉ (C ₃ H ₇ )-(propylcyclohexyl); -C ₆ H ₉ (C ₄ H ₉ )-(butylcyclohexyl); -C ₆ H ₈ (CH ₃ ) ₂ -(dimethylcyclohexyl); -C ₆ H ₉ (OH)-(hydroxycyclohexyl); -C ₇ H ₁₂ -(cycloheptyl);

(piperazinyl);

(1,4-Diazabicyclo[2.2.2]octyl).

Preferably, the terminal group Z in the substituent R in the formula (3) is: -H; -CH ₃ ; -C ₂ H ₅ ; -C ₃ H ₇ ; -C ₄ H ₉ ; -C ₅ H ₁₁ ;-C ₆ H ₁₃ ; -OCH ₃ ; -OC ₂ H ₅ ; -OC ₃ H ₇ ; -OC ₄ H ₉ ; -OC ₅ H ₁₁ ; -OC ₆ H ₁₃ ; -C ₆ H ₅ ; -C ₅ H ₄ N; -OH, -NH ₂ ; -SH; -COOH; -COOCH ₃ ; -COOC ₂ H ₅ ; -SO ₃ H; -C ₅ H ₄ N ⁺ ; -N ⁺ (CH ₃ ) ₃ ;- N ⁺ (C ₂ H ₅ ) ₃ ; -N ⁺ (C ₃ H ₇ ) ₃ ; -N ⁺ (C ₄ H ₉ ) ₃ ; -N ⁺ (C ₅ H ₁₁ ) ₃ ; -N ⁺ (C ₆ H ₁₃ ) ₃ ; -N ⁺ (CH ₃ ) ₂ (C ₂ H ₅ ); -N ⁺ (CH ₃ ) ₂ (C ₃ H ₇ ); -N ⁺ (CH ₃ ) ₂ (C ₄ H ₉ ); N ⁺ (CH ₃ ) ₂ (C ₅ H ₁₁ ); -N ⁺ (CH ₃ ) ₂ (C ₆ H ₁₃ ); -N ⁺ (CH ₃ ) ₂ (C ₇ H ₁₅ ); -N ⁺ (CH _{3 2} (C ₈ H ₁₇ ); -N ⁺ (CH ₃ ) ₂ (C ₉ H ₁₉ ); -N ⁺ (CH ₃ ) ₂ (C ₁₀ H ₂₃ ); -N ⁺ (CH ₃ ) ₂ (C ₁₁ H ₂₃ ); -N ⁺ (CH ₃ ) ₂ (C ₁₂ H ₂₅ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₃ H ₇ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₄ H ₉ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₅ H ₁₁ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₆ H ₁₃ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₇ H ₁₅ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₈ H ₁₇ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₉ H ₁₉ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₁₀ H ₂₃ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₁₁ H ₂₃ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₁₂ H ₂₅ );

(1,4-Diazabicyclo[2.2.2]octyl); or a quaternary ammonium salt having a terminal group containing a hydroxyl group, a carboxylic acid group, a sulfonic acid group or a carboxylic acid ester.

Preferably, the structural formula of the hypocrellin derivative of the formula (1) further comprises an enol tautomer represented by the formula (1'); and the hypocrellin derivative of the formula (2) The structural formula further comprises an enol tautomer represented by formula (2'):

In order to achieve the above second object, the present invention adopts the following technical solutions:

A method for preparing a hyalin derivative nano-assembly is as follows: a hypocrellin derivative molecule or a compound of a hyalin derivative and another amphiphilic molecule is dissolved in an organic solvent (methanol, acetonitrile, chloroform) Or tetrahydrofuran), then added dropwise to a pure aqueous solution, a buffer solution of different pH (2-9) or an aqueous solution containing a hydrophilic polymer (PEG, PVA, etc.), and stirred at room temperature for 2-24 hours, then the organic solvent is removed and separated. After purification, the hypocrellin nanoassembly is obtained.

In order to achieve the above third object, the present invention adopts the following technical solutions:

A hypocrellin derivative nanoassembly is used as a photosensitizer preparation for photodynamic therapy for treating tumors.

Preferably, the photodynamic therapy for treating a tumor is to enter the hyalin derivative nano-assembler photosensitizer preparation into the blood circulation system of the living body by intravenous injection for photodynamic therapy.

The beneficial effects of the present invention are as follows:

1) A method for synthesizing and separating a hyalin derivative, such as a nanosphere, a nanorod, a nanotube, a nanosheet, a nanocapsule or a nanocapsule, etc., in the present invention Simple, no expensive reaction materials and complicated separation means, low cost, large amount of preparation, small toxic and side effects, easy to metabolize;

2) The absorption frequency of the hypocrellin derivative nanoassembly in the present invention is red-shifted by more than 50 nm in the maximum absorption wavelength compared with the precursor hypocrellin derivative, and is in the near-infrared absorption between 650 and 850 nm. It has good light stability, strong anti-bleaching ability and better biocompatibility; it can effectively produce active oxygen under the stimulation of near-infrared light (650-850nm), which can kill tumor cells;

3) The hypocrellin derivative nanoassemblies of the present invention can be concentrated to the lesion site by intravenous injection, and can efficiently generate active oxygen under the stimulation of near-infrared light (650-850 nm), and can kill tumor cells.

DRAWINGS

The specific embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

Fig. 1 shows the structural formula of the amphiphilic derivative of the amphiricin derivatives HB-1 to HB-126 used in the present invention.

2 is a transmission electron micrograph of a hypocrellin nanocapsule prepared in Example 16 of the present invention.

Fig. 3 is a graph showing the absorption of the hypocrellin nanocapsules and the hypocrellin precursor prepared in Example 16 of the present invention.

Figure 4 is a graph showing the photoactive oxygen generation of the hypocrellin nanovesicles prepared in Example 16 of the present invention.

Figure 5 is a graph showing the dark toxicity and phototoxicity of the hypocrellin nanovesicles prepared in Example 16 of the present invention.

detailed description

In order to explain the present invention more clearly, the present invention will be further described in conjunction with the preferred embodiments and the accompanying drawings. Similar components in the drawings are denoted by the same reference numerals. It should be understood by those skilled in the art that the following detailed description is intended to be illustrative and not restrictive.

Example 1

10 mg of HB-1 was dissolved in 5 mL of tetrahydrofuran, and then quickly injected into 20 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, it was purified by dialysis to obtain a water-soluble hyalin nanosheet having a size of 50 nm. The absorption wavelength is 650 nm.

Example 2

10 mg of HB-5 was dissolved in 5 mL of chloroform, and then quickly injected into 20 mL of buffer solution (Ph=7), and rapidly stirred at room temperature for 24 hours. After removing chloroform, dialysis was carried out to obtain a water-soluble hyalin nanorod. The length is 200 nm, the diameter is 30 nm, and the maximum absorption wavelength is 650 nm.

Example 3

5 mg of HB-12 was dissolved in 5 mL of tetrahydrofuran, and then quickly injected into 20 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, it was purified by dialysis to obtain water-soluble hyalin nanospheres having a size of 60 nm. The absorption wavelength was 660 nm.

Example 4

8mg of HB-1 was dissolved in 5mL of acetonitrile, then quickly injected into 10mL of pure water, stirred rapidly for 8 hours at room temperature, after removing acetonitrile, dialysis and purification, to obtain water-soluble hypocrellin nanotubes, length 300nm, diameter 40 nm, the maximum absorption wavelength is 650 nm.

Example 5

5 mg of HB-35 was dissolved in 10 mL of chloroform, and then added dropwise to a 10 mL aqueous solution containing 5 mg of polyethylene glycol (PEG), and rapidly stirred at room temperature for 12 hours. After removing chloroform, dialysis was carried out to obtain a water-soluble bamboo red. The microcapsules have a size of 120 nm and a maximum absorption wavelength of 710 nm.

Example 6

10 mg of HB-54 was dissolved in 5 mL of tetrahydrofuran, then quickly injected into 10 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, it was purified by dialysis to obtain water-soluble hypocrellin nanocapsules having a size of 110 nm. The maximum absorption wavelength is 670 nm.

Example 7

10 mg of HB-63 was dissolved in 5 mL of chloroform, then quickly injected into 20 mL of buffer solution (pH=7), and rapidly stirred at room temperature for 10 hours. After removing chloroform, dialysis and purification were carried out to obtain water-soluble hyalin nanospheres. The size is 50 nm and the maximum absorption wavelength is 680 nm.

Example 8

5 mg of HB-72 was dissolved in 5 mL of tetrahydrofuran, and then quickly injected into 20 mL of pure water. The mixture was rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, it was purified by dialysis to obtain a water-soluble hypocrellin nanotube with a length of 300 nm. At 30 nm, the maximum absorption wavelength is 660 nm.

Example 9

8mg of HB-86 was dissolved in 5mL of acetonitrile, then quickly injected into 10mL of pure water, stirred rapidly for 12 hours at room temperature, acetonitrile was removed, and purified by dialysis to obtain water-soluble hyalin nanosheets with a size of 80nm. The absorption wavelength was 660 nm.

Example 10

5 mg of HB-105 was dissolved in 10 mL of chloroform, and then added dropwise to 10 mL of an aqueous solution containing 5 mg of polyvinyl alcohol (PVA), and rapidly stirred at room temperature for 24 hours. After removing chloroform, dialysis was carried out to obtain a water-soluble Rhodobacter sphaeroides. The nanorods have a length of 300 nm, a diameter of 30 nm, and a maximum absorption wavelength of 760 nm.

Example 11

5 mg of HB-3 and 5 mg of PLGA-PEG were dissolved in 5 mL of tetrahydrofuran, and then quickly injected into 20 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, dialysis and purification were carried out to obtain water-soluble hypocrellin nanocapsules. The size is 150 nm and the maximum absorption wavelength is 760 nm.

Example 12

10 mg of HB-7 and 20 mg of PBLG-PEG were dissolved in 5 mL of chloroform, then quickly injected into 20 mL of buffer solution (Ph=7), and rapidly stirred at room temperature for 6 hours. After removal of chloroform, dialysis was carried out to obtain water-soluble bamboo. The erythromycin nanovesicle has a size of 170 nm and a maximum absorption wavelength of 660 nm.

Example 13

5 mg of HB-13 and 10 mg of PAA-b-PS were dissolved in 5 mL of tetrahydrofuran, then quickly injected into 20 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, dialysis and purification were carried out to obtain water-soluble hypocrellin. The nanorods have a length of 300 nm, a diameter of 50 nm, and a maximum absorption wavelength of 660 nm.

Example 14

8 mg of HB-8 and 5 mg of PB-b-PAA were dissolved in 5 mL of acetonitrile, then quickly injected into 10 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing acetonitrile, dialysis was carried out to obtain water-soluble hypocrellin. The nanorods have a length of 500 nm, a diameter of 60 nm, and a maximum absorption wavelength of 660 nm.

Example 15

5 mg of HB-32 and 20 mg of PDMS-b-PEO were dissolved in 10 mL of chloroform, then added dropwise to 10 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing chloroform, dialysis was carried out to obtain water-soluble Rhodobacter sphaeroides. The nanospheres have a size of 70 nm and a maximum absorption wavelength of 660 nm.

Example 16

10 mg of HB-57 and 10 mg of the polypeptide were dissolved in 5 mL of tetrahydrofuran, and then rapidly injected into 10 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, dialysis and purification were carried out to obtain water-soluble hypocrellin nanovesicles. Transmission electron microscopy showed that the size of the nanovesicles was around 150 nm (Fig. 2) and the maximum absorption wavelength was 660 nm. Compared with the hypocrellin precursor molecule, the maximum absorption peak of the hypocrellin nanovesicles is red-shifted by nearly 50 nm (Fig. 3); the photostability is greatly improved; under 671 nm laser irradiation (30 mW/cm ² ), Effectively produced singlet oxygen (Figure 4); cell dark toxicity and phototoxicity tests showed (Figure 5) that the dark toxicity of the hypocrellin nanovesicles was very low, but at 671 nm laser irradiation (30 mW/cm ² ) for 10 minutes, 100 ug /mL of erythromycin vesicles can completely kill cancer cells.

Example 17

10 mg of HB-68 and 20 mg of PS-b-PEO were dissolved in 5 mL of chloroform, then quickly injected into 20 mL of buffer solution (pH=7), rapidly stirred at room temperature for 8 hours, chloroform was removed, and purified by dialysis to obtain water-soluble The hypocrellin nanotubes have a length of 400 nm, a diameter of 30 nm, and a maximum absorption wavelength of 710 nm.

Example 18

5 mg of HB-78 and 5 mg of PS-b-PEO were dissolved in 10 mL of tetrahydrofuran, and then quickly injected into 20 mL of pure water, and rapidly stirred at room temperature for 12 hours. After removing tetrahydrofuran, dialysis and purification were carried out to obtain water-soluble hypocrellin. The nanorods have a length of 600 nm, a diameter of 80 nm, and a maximum absorption wavelength of 760 nm.

Example 19

8mg of HB-88 and 10mg of PS-b-PEG were dissolved in 5mL of acetonitrile, then quickly injected into 10mL of pure water, stirred rapidly for 12 hours at room temperature, acetonitrile was removed, and purified by dialysis to obtain water-soluble hypocrellin. The nanospheres have a size of 100 nm and a maximum absorption wavelength of 690 nm.

Example 20

5 mg of HB-102 and 10 mg of PLGA-b-PEG were dissolved in 10 mL of chloroform, then added dropwise to 10 mL of an aqueous solution containing 5 mg of polyvinyl alcohol (PVA), and rapidly stirred at room temperature for 10 hours to remove chloroform and then dialyzed. Purified to obtain a water-soluble hypocrellin nanotube having a length of 200 nm, a diameter of 30 nm, and a maximum absorption wavelength of 670 nm.

Example 21

5 mg of HB-23 and 5 mg of bovine serum albumin (BSA) were dissolved in 10 mL of chloroform, and then added dropwise to a 10 mL aqueous solution containing 5 mg of polyvinyl alcohol (PVA), and rapidly stirred at room temperature for 20 hours to remove chloroform. The dialysis was purified to obtain a water-soluble hypocrellin nanocapsule having a size of 180 nm and a maximum absorption wavelength of 700 nm.

Example 22

5 mg of HB-112 and 10 mg of PLGA-b-PEG were dissolved in 10 mL of chloroform, and then added dropwise to 10 mL of an aqueous solution containing 5 mg of polyvinyl alcohol (PVA), and rapidly stirred at room temperature for 10 hours to remove chloroform and then dialyzed. Purification to obtain a water-soluble hypocrellin nanorod having a length of 800 nm, a diameter of 60 nm, and a maximum absorption wavelength of 760 nm.

Example 23

5 mg of HB-123 and 10 mg of PLGA-b-PEG were dissolved in 10 mL of chloroform, then added dropwise to an aqueous solution containing 10 mL, and rapidly stirred at room temperature for 10 hours. After removing chloroform, dialysis was carried out to obtain a water-soluble Rhodobacter sphaeroides. The nanospheres have a size of 80 nm and a maximum absorption wavelength of 720 nm.

Example 24

Dark toxicity and phototoxicity experiments of cells: The cultured Hela cells were digested with 0.25% trypsin and pipetted to prepare a single cell suspension. The number of cells was adjusted to about 2×10 ⁴ cells/mL, and 200 uL per well was seeded in a 96-well culture plate. Incubate in an incubator containing 5% CO ₂ at 37 °C. After the cells are attached to the wall, the supernatant culture solution is discarded, and the different concentrations of the hypocrellin nanoassembly are added in strict accordance with the experimental design, and placed in an incubator containing 5% CO ₂ at 37 ° C to continue the culture incubation 1 hour. Then, the laser is irradiated with a wavelength of 671 nm semiconductor light, and the power density is adjusted to 30 mW/cm ² , so that the light beam is uniformly and vertically irradiated onto the 96-well culture plate, and the irradiation time is 1000 S, and each 96-well culture plate is provided with a blank group, each of which is provided with a blank group. The condition is 6 holes. After illuminating, the cells were incubated in an incubator containing 5% CO ₂ at 37 ° C for 24 hours, and then the cell survival rate was measured by MTT assay.

Comparative example 1

A nano-assembly is prepared in the same manner as in the embodiment 20, wherein the precursor is iron phthalocyanine and the amphiphilic molecule PLGA-b-PEG. After the reaction is purified, the nanostructure obtained by the test is a nanorod with a maximum absorption wavelength of 765 nm. It has good light stability and low dark toxicity to cells. As in Example 24, it was irradiated with a laser having a power density of 30 mW/cm ² , and no phototoxicity was observed.

Comparative example 2

A nano-assembly prepared in the same manner as in Example 10, wherein the precursor is changed to Hypocrellin A or Hypocrellin B and polyvinylpyrrolidone (PVP, a water-soluble surfactant), and the reaction is carried out. After purification, it was found that the hypocretin nanospheres were formed with a size of about 60 nm and a large absorption wavelength of 470 nm. Under 671 nm laser irradiation (30 mW/cm ² ), singlet oxygen could not be produced. Therefore, under these conditions, there is no phototoxicity to cancer cells.

Conclusion: The hypocrellin derivative nanoassembly of the present invention uses a hypocrellin derivative as a precursor, or a hypocrellin derivative and a parent molecule as a precursor, and the maximum absorption wavelength ranges from 650 to 850 nm, and the light is stable. Good sex, strong anti-bleaching ability, can effectively produce active oxygen under the stimulation of near-infrared light, can kill tumor cells, lack hypocrellin derivatives, or use other reagents instead of amphiphilic molecules to make nano-assemblies in some There are different degrees of weakening. The product synthesis and separation method of the invention is simple, low in cost, can be prepared in a large amount, has small toxic and side effects, and is easy to be metabolized.

It is apparent that the above-described embodiments of the present invention are merely illustrative of the present invention and are not intended to limit the embodiments of the present invention, and those skilled in the art can also make the above description. It is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention.

Claims (10)

1. A hypocrellin derivative nano-assembly, characterized in that the hypocrellin derivative nano-assembly is prepared by using a erythromycin derivative as a precursor, and the size is 20-200 nm and the maximum absorption is obtained. Nanoassemblies with wavelengths ranging from 650 to 850 nm.
2. The hypocrellin derivative nanoassembly according to claim 1, wherein the hypocrellin derivative nanoassembly is prepared by using a erythromycin derivative and a parent molecule as a precursor. A nanoassembly having a size of 20-200 nm and a maximum absorption wavelength in the range of 650-850 nm was obtained.
3. The hypocrellin derivative nanoassembly according to claim 1, wherein the hypocrellin derivative is a polysubstituted near-infrared lutein derivative and a long-chain quaternary ammonium salt. Hypocrellin derivative or ester water amphiphilic rhodamine derivative.
4. The hypocrellin derivative nanoassembly according to claim 2, wherein the amphiphilic molecule is a high molecular polymer, a protein, a polypeptide, a deoxyribonucleic acid or a nucleic acid aptamer, and the molecular weight thereof is 1000. Between -100000; preferably, the high molecular polymer is polylactic acid-polyethylene glycol, polylactic acid-polyethylene glycol-polylactic acid, polyacrylic acid-b-polybutadiene, polyglutamic acid benzyl ester - polyethylene glycol, polystyrene-b-polyvinyl ester, polystyrene-b-polydimethylsiloxane, polystyrene-b-polyethylene glycol diethylene glycol, polyacrylic acid-b- Polystyrene, polystyrene-b polyethylene oxide or polydimethylsiloxane-b-polyethylene oxide.
5. The hypocrellin derivative nanoassembly according to claim 3, wherein the hypocrellin derivative has the structural formula of formula (1) or formula (2):

   

   In formulas (1) and (2), T ₁ represents that two adjacent R ₂ and R ₃ , R ₄ and R _{5 are} not connected or have one group connected or two groups are connected; when two adjacent R ₂ When R ₃ or R ₄ and R _{5 are} not linked, R ₂ and R ₅ are oxygen, and R ₃ and R ₄ are hydrogen; when two adjacent R ₂ and R ₃ or R ₄ and R ₅ are bonded, They constitute a substituted or unsubstituted six-membered heterocyclic ring, wherein T ₁ is a substituted or unsubstituted linker containing two carbon atoms, R ₂ , R ₅ are nitrogen, R ₃ and R ₄ are sulfur; carbon atoms 13, 14 And the dotted line of 15 digits indicates that the double bond position is in the 13-14 position or the 14-15 position;

   In the formula (1), R ₁ is -H, -COCH ₃ or -C(CH ₃ )=N-R; in the formula (2), R ₁ is -H or -COCH ₃ ; T ₂ represents R ₈ and R ₉ linked or unconnected: when R ₈ and R _{9 are} bonded, they form a substituted or unsubstituted five-membered ring, six-membered ring or seven-membered ring, wherein T ₂ is substituted or unsubstituted with one, two or three One carbon atom linker;

   When two adjacent R ₂ and R ₃ or R ₄ and R _{5 in the} formula (1) are not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is hydrogen, the double bond is located. C ₁₃ = C ₁₄ or C ₁₄ = C _{15 of} three carbon atoms of C ₁₃ , C ₁₄ , C ₁₅ labeled in formula (1); two adjacent R ₂ and R ₃ or R in formula (1) ₄ and R _{5 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is -COCH ₃ or -C(CH ₃ )=NR, the double bond is located in formula (1) C ₁₃ = C _{14 of} three carbon atoms labeled C ₁₃ , C ₁₄ , C ₁₅ ;

   In the formula (2), two adjacent R ₂ and R ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is In the case of hydrogen, the double bond is located at C ₁₃ = C ₁₄ or C ₁₄ = C _{15 of} three carbon atoms of C ₁₃ , C ₁₄ , C ₁₅ labeled in formula (2); two adjacent R in formula (2) ₂ and R ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen and R ₁ is -COCH ₃ , the double bond is at the formula (2) C ₁₃ , C ₁₄ , C ₁₅ three carbon atoms labeled C ₁₃ = C ₁₄ ;

   In the formula (1), R is a substituent, and the substituent R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; the hydrophobic group contains an alkyl group, an alkenyl group, Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, phenyl or heterocyclic; the hydrophilic group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a polyethylene glycol a quaternary or quaternary ammonium salt; the structural formula of the substituent R is as shown in formula (3):

   

   In the formula (3), 0≤m≤12, 0≤n≤500, 0≤p≤12, 0≤q≤12, 0≤r≤1; the m, n, p, q, r are zero or a positive integer; Y is a linking group; Z is a terminal group; (OCH ₂ CH ₂ ) _n is a polyethylene glycol unit;

   The linking group Y in the formula (3) is NH, O, S, a carboxylate, an amide, a sulfocarboxylate, an aryl group, a heterocyclic aryl group, a hydrocarbon group of 3 to 12 carbon atoms or a cyclic hydrocarbon group of 3 to 12 carbon atoms. ;

   The aryl group is a substituted or unsubstituted aryl group; the heterocyclic aryl group is a substituted or unsubstituted heterocyclic aryl group; the hydrocarbon group of 3 to 12 carbon atoms contains a substituted or unsubstituted or hetero atom-containing olefin or alkyne; The cycloalkyl group of 3 to 12 carbon atoms comprises a substituted or unsubstituted or heteroatom-containing cycloalkane, cycloalkene or cycloalkyne; the hetero atom is an oxygen, nitrogen or sulfur atom; the substituent is 1 to 12 carbon atoms An alkyl group, an alkenyl group of 2 to 12 carbon atoms, an alkynyl group of 2 to 12 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, an aryl group or an aralkyl group of 6 to 12 carbon atoms; An alkyl group having a hydroxyl group, a carboxylic acid group, a sulfonic acid group or a carboxylic acid ester; or an alkyl group, an alkenyl group, an alkynyl group or a ring having a chain length of 1 to 12 carbon atoms in which the hetero atom is an oxygen, nitrogen or sulfur atom; An alkyl group, an aryl group or an aralkyl group; or a different combination of the above substituents;

   The terminal group Z in the formula (3) is hydrogen, an alkyl group of 1 to 12 carbon atoms, an alkoxy group of 1 to 12 carbon atoms, a phenyl group, a heterocyclic ring, a hydroxyl group, a decyl group, a carboxylic acid group, a sulfonic acid group or a pyridine group. salt;

   When the terminal group Z in the formula (3) is a pyridinium salt, the substituent on the pyridine ring in the pyridinium salt is in the ortho, meta or para position; the pyridinium salt is composed of pyridine and a chain length of 1-12 The quaternization of a halogenated hydrocarbon of a carbon atom; the anion in the pyridinium salt is an anion permitted by the pharmaceutical preparation;

   The three substituents R ₁₂ , R ₁₃ and R _{14 in the} formula (3) are independently or simultaneously: an alkyl group of 1 to 12 carbon atoms, an alkenyl group of 2 to 12 carbon atoms, 2 to 12 carbons. An alkynyl group of an atom, a cycloalkyl group of 3 to 8 carbon atoms, a cycloalkenyl group of 3 to 8 carbon atoms, an aryl group or an aralkyl group of 6 to 12 carbon atoms; or a terminal group containing a hydroxyl group or a carboxylic acid group An alkyl group of a sulfonic acid group or a carboxylic acid ester; or an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or an aralkyl group having a chain length of 1 to 12 carbon atoms containing a hetero atom of oxygen, nitrogen or a sulfur atom; ; or a combination of these different substituents; quaternary ammonium salt of the anion X ^- is the anion of a pharmaceutical formulation allowed;

   In the formula (1), two adjacent R ₂ and R ₃ or R ₄ and R _{5 are} not connected and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, R ₁ is -COCH ₃ and a double bond. When C ₁₃ = C ₁₄ , the substituent R in the formula (1) does not comprise the following structure: -(CH ₂ ) _m -NH-(CH ₂ ) _p -Z; wherein 1 ≤ m ≤ 12, 0 ≤ _p ≤ 12, Z is a hydroxyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester.

   R ₆ to R ₁₁ on the hypocrellin and piperazine ring in the formula (2) are all subordinate to the substituent R; the substituent R is a hydrophobic group, a hydrophilic group or a hydrophobic group and a hydrophilic group. Different combinations of groups; the hydrophobic group containing an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic group; the hydrophilic group having a hydroxyl group or a carboxyl group , an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycolated group, a quaternary ammonium salt or a pyridinium salt; the structural formula of the substituent R is as shown in the formula (3);

   In the formula (2), two adjacent R ₂ and R ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not connected and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, and R ₁ is When hydrogen and a double bond are located at C ₁₄ =C ₁₅ , at least one of the two carbon atoms a and b on the piperazine ring of formula (2) is a tertiary carbon atom; two adjacent R ₂ and R in formula (2) ₃ or R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen, R ₃ and R ₄ are hydrogen, R ₁ is -COCH ₃ and the double bond is at C ₁₃ =C ₁₄ . At least one of the two carbon atoms a and b on the piperazine ring of formula (2) is a tertiary carbon atom;

   The structural formula of the hypocrellin derivative of the formula (1) further comprises an enol tautomer represented by the formula (1'); and the structural formula of the hypocrellin derivative of the formula (2) Also included are the enol tautomers represented by formula (2'):

   
6. The hypocrellin derivative nanoassembly according to claim 5, wherein T1 of the hypocrellin derivative in the formula (1) is acyclically linked, and its structural formula is as follows ( 4) shown:

   

   In the formula (1), the two adjacent R ₂ and R ₃ or R ₄ and R _{5 of the} erythromycin are not linked and R ₂ and R ₅ are oxygen and R ₃ and R ₄ are hydrogen, and the structural formula thereof As shown in formula (4);

   The substituent R ₁ of the hypocrellin derivative in the formula (4) is H, -COCH ₃ or -C(CH ₃ )=NR; when the R ₁ is H, the double bond is in the formula (4) marked C _13, C _14, C ₁₅ of three carbon atoms C ₁₃ = C ₁₄ or C ₁₄ = C _15; said R ₁ is -COCH ₃ or -C (CH ₃₎ = NR, double bond is located (4) noted in the formula C _13, C _14, C C ₁₅ carbon atoms and three ₁₃ = C _14;

   The structural formula of the substituent R in the formula (4) is as shown in the formula (3), and the substituent R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; The group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, a phenyl group or a heterocyclic ring; the hydrophilic group contains a hydroxyl group, a carboxyl group, an ester group, an amide group or a carboxylic acid group. , sulfonic acid group, ethylene glycol group or quaternary ammonium salt;

   In the above formula (4), the substituent R ₁ is H and the double bond is substituted at the C ₁₄ =C ₁₅ position (formula 4b) or R ₁ is -COCH ₃ and the double bond is at the C ₁₃ =C ₁₄ position (formula 4c). The radical R does not comprise the following structure: -(CH ₂ ) _m -NH-(CH ₂ ) _p -Z; wherein 1 ≤ m ≤ 12, 0 ≤ _p ≤ 12, Z is a hydroxyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester.
7. The hypocrellin derivative nanoassembly according to claim 5, wherein both T1 and T2 in the formula (2) are non-cyclically connected, and the structural formula is as shown in the formula (5). :

   

   In formula (2), two adjacent R ₂ and R ₃ , R ₄ and R ₅ or R ₈ and R _{9 are} not linked and R ₂ and R ₅ are oxygen and R ₃ and R ₄ are Hydrogen, the structural formula of which is represented by formula (5);

   The substituent R ₁ of the piperazine derivative of the formula (5) is H or -COCH ₃ ; when the R ₁ is H, the double bond is located at C ₁₃ and C as indicated in the formula (5). ₁₄ , C ₁₃ three carbon atoms of C ₁₃ = C ₁₄ or C ₁₄ = C ₁₅ ; when R ₁ is -COCH ₃ , the double bond is located in the formula (5) labeled C ₁₃ , C ₁₄ , C ₁₅ C ₁₃ = C _{14 of} three carbon atoms;

   In the above formula (5), when the substituent R ₁ is H and the double bond is at the C ₁₄ =C ₁₅ position, at least one of the two carbon atoms a and b on the piperazine ring of the formula (5b) is a tertiary carbon atom; When (5) the substituent R ₁ is -COCH ₃ and the double bond is at the C ₁₃ =C ₁₄ position, at least one of the two carbon atoms a and b on the piperazine ring of the formula (5c) is a tertiary carbon atom;

   The substituents R ₆ to R ₁₁ in the formula (5) are all defined by the substituent R in the formula (3), and the substituents R ₆ to R _{11 are} partially or wholly the same or completely different; the substituent R ₆ ～ R ₁₁ is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; the hydrophobic group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or a heterocyclic ring; The group contains a hydroxyl group, a carboxyl group, an ester group, an ether group, an amide group, a sulfonic acid group, an ethylene glycol unit or a quaternary ammonium salt.
8. A hypocrellin derivative nanoassembly according to claim 5, wherein T1 in the formula (1) and the formula (2) is a substituted or unsubstituted connection having two carbon atoms. a structure having a structure represented by the formula (6): wherein the substituents R ₁₅ to R ₁₈ are independently or simultaneously the R substituent in the formula (3) in claim 1; R ₈ and R in the formula (2) _{9. When} T2 constitutes a substituted or unsubstituted five-membered ring, six-membered ring or seven-membered ring, as shown in formula (7):

   

   Wherein ring A is a saturated or unsaturated 5-, 6-, or 7-membered heterocyclic ring or a non-heterocyclic ring, and the substituents on the ring are independently or simultaneously the R substituent in the formula (3) in claim 1; R is a hydrophobic group, a hydrophilic group or a different combination of a hydrophobic group and a hydrophilic group; the hydrophobic group contains an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, Phenyl or heterocyclic; the hydrophilic group containing a hydroxyl group, a carboxyl group, an ester group, an amide group, a carboxylic acid group, a sulfonic acid group, a glycol group or a quaternary ammonium salt.
9. A hypocrellin derivative nanoassembly according to claim 5, wherein the linker Y in the substituent R in the formula (3) is: -NH-; -O-, -S -; -COO-;CONH-;-SO ₃ -; -CH=CH-;-C≡C-;-C ₆ H ₄ -(phenyl);-C ₆ H ₃ (CH ₃ )-; ₆ H ₃ (C ₂ H ₅ )-; -C ₆ H ₃ (OH)-; -C ₆ H ₃ (F)-; -C ₆ H ₃ (Cl)-; -C ₆ H ₃ (Br)- ;-C ₅ H ₃ N-(pyridyl); -C ₃ H ₄ -(cyclopropyl); -C ₄ H ₆ -(cyclobutyl); -C ₅ H ₈ -(cyclopentyl);- C ₅ H ₇ (CH ₃ )-(methylcyclopentyl); -C ₅ H ₇ (OH)-(hydroxycyclopentyl); -C ₆ H ₁₀ -(cyclohexyl); -C ₆ H ₉ ( CH ₃ )-(methylcyclohexyl); -C ₆ H ₉ (C ₂ H ₅ )-(ethylcyclohexyl); -C ₆ H ₉ (C ₃ H ₇ )-(propylcyclohexyl); C ₆ H ₉ (C ₄ H ₉ )-(butylcyclohexyl); -C ₆ H ₈ (CH ₃ ) ₂ -(dimethylcyclohexyl); -C ₆ H ₉ (OH)-(hydroxycyclohexyl); -C ₇ H ₁₂ -(cycloheptyl);

   

   (piperazinyl);

   

   (1,4-diazabicyclo[2.2.2]octyl);

   The terminal group Z in the substituent R in the formula (3) is: -H; -CH ₃ ; -C ₂ H ₅ ; -C ₃ H ₇ ; -C ₄ H ₉ ; -C ₅ H ₁₁ ;-C ₆ H ₁₃ ; -OCH ₃ ; -OC ₂ H ₅ ; -OC ₃ H ₇ ; -OC ₄ H ₉ ; -OC ₅ H ₁₁ ; -OC ₆ H ₁₃ ; -C ₆ H ₅ ; -C ₅ H ₄ N ;-OH,-NH ₂ ;-SH;-COOH;-COOCH ₃ ;-COOC ₂ H ₅ ;-SO ₃ H;-C ₅ H ₄ N ⁺ ;-N ⁺ (CH ₃ ) ₃ ;-N ⁺ ( C ₂ H ₅ ) ₃ ; -N ⁺ (C ₃ H ₇ ) ₃ ; -N ⁺ (C ₄ H ₉ ) ₃ ; -N ⁺ (C ₅ H ₁₁ ) ₃ ; -N ⁺ (C ₆ H ₁₃ ) ₃ ;-N ⁺ (CH ₃ ) ₂ (C ₂ H ₅ ); -N ⁺ (CH ₃ ) ₂ (C ₃ H ₇ ); -N ⁺ (CH ₃ ) ₂ (C ₄ H ₉ ); -N ⁺ ( CH ₃ ) ₂ (C ₅ H ₁₁ ); -N ⁺ (CH ₃ ) ₂ (C ₆ H ₁₃ ); -N ⁺ (CH ₃ ) ₂ (C ₇ H ₁₅ ); -N ⁺ (CH ₃ ) ₂ ( C ₈ H ₁₇ ); -N ⁺ (CH ₃ ) ₂ (C ₉ H ₁₉ ); -N ⁺ (CH ₃ ) ₂ (C ₁₀ H ₂₃ ); -N ⁺ (CH ₃ ) ₂ (C ₁₁ H ₂₃ ) ;-N ⁺ (CH ₃ ) ₂ (C ₁₂ H ₂₅ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₃ H ₇ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₄ H ₉ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₅ H ₁₁ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₆ H ₁₃ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₇ H ₁₅ ) ;-N ⁺ (C ₂ H ₅ ) ₂ (C ₈ H ₁₇ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₉ H ₁₉ ); -N ⁺ (C ₂ H ₅ ) ₂ (C ₁₀ H ₂₃ ) ^{_{-N + (C 2 H 5)}} 2 (C 11 H 23); - N + (C 2 H 5) 2 (C 12 H 25);

   

   (1,4-Diazabicyclo[2.2.2]octyl); or a quaternary ammonium salt having a terminal group containing a hydroxyl group, a carboxylic acid group, a sulfonic acid group or a carboxylic acid ester.
10. A use of a rhodamine derivative nanoassembly according to any of claims 1-9 as a photosensitizer formulation for photodynamic therapy for treating tumors.

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